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An Effective Method for Lovastatin Production by Fungi Over Submerged Fermentation

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An Effective Method for Lovastatin Production by Fungi Over Submerged Fermentation View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by ePrints@Bangalore University E3 Journal of Biotechnology and Pharmaceutical Research Vol. 3(2), pp. 15-21, April 2012 Available online at http://www.e3journals.org/JBPR ISSN 2141-7474 © 2012 E3 Journals Mini Review Solid state fermentation: An effective method for Lovastatin production by fungi over submerged fermentation Praveen VK and Savitha J* Department of Microbiology and Biotechnology, Bangalore University, Jnana Bharathi Campus, Bangalore-560056. India. Accepted 13 March, 2012 The Enzyme 3-hydroxy-3-methylglutaryl-CoA reductase (HMG CoA reductase) catalyses conversion of HMG CoA to mevalonate during cholesterol biosynthesis. Lovastatin is used as an anti-cholesterol drug which blocks HMG CoA reductase activity. Lovastatin has been reported to be produced by Submerged Fermentation (SmF) and Solid State Fermentation (SSF) by fungi. Of-late it is used not only as anti- cholesterol drug but as anti-inflammatory agent, cancer cell apoptosis, restoration of renal function, bone disorders treatment; immune-modulatory role is also being investigated. This review provides insight into the different lovastatin production strategies employed by SSF, its advantages over SmF, optimisation parameters, lovastatin genetics etc. Key words: HMG CoA. Lovastatin, Fungi, SSF, SmF, Pleiotropic. INTRODUCTION The World Health Organization estimated that 17.3 antibiotic and other related pharmacological properties million lives were lost in 2008 and an expected 23.6 (Bedford et al., 1995). Noted among the fungal million people will die of cardiovascular diseases (CVD) metabolites are statins (anti-cholesterol compounds) that by the year 2030 (WHO, 2011). Close to 80% of mortality are considered as the most important class produced by rates were reported from the lower and middle income the polyketide pathway. Statins comprises of Compactin, countries. Hypercholesterolemia is one of the reasons for lovastatin, pravastatin, simvastatin, rosuvastatin, these deaths. The treatment of the hypercholesterolemia atorvastatin and fluvastatin. Compactin and lovastatin are is targeted by decreasing the low density lipoprotein of biological origin whereas simvastatin, pravastatin, (LDL) cholesterol and is best achieved by medications rosuvastatin etc are chemical modifications of compactin when diet and exercise fail (Lloyd-Jones et al.,2009) . A and lovastatin (Chakravarti and Sahai, 2004). The wide variety of biologically active compounds are biosynthetic pathway involved in statin production starts produced by fungi, a large proportion of which are from acetate units linked to each other in a head to- tail produced by the polyketide biosynthetic pathway. Fungal fashion to form a polyketide chain. Lovastatin (Figure 1) polyketides represent structurally diverse group and with prevents formation of mevalonate from HMG Co-A many displaying important biological activities such as (Sreenivasan et al., 2008; Marcin and Stanislaw, 2009) by competitively inhibiting the enzyme HMG CoA Reductase. Lovastatin can exist in two forms i.e hydroxyl from and lactone form, of which the hydroxyl-form is the *Corresponding author. Email: [email protected]. Tel: +91-80- active drug. The lactone forms (e.g. lovastatin, 22961461. Fax: +918023219295 simvastatin, cerivastatin) are lipophilic while the acid E3 J. Biotechnol. Pharm. Res. 16 production of Mevinolin (Lovastatin) from Aspergillus terreus. It was later discovered that in fact what they referred to as lymphomas associated with compactin were actually the accumulation of reductase proteins in endoplasmic reticulum in response to statin therapy., Merck got the approval from Food and Drug Administration (FDA) in 1987 to release Mevinolin into the market. However, Akira Endo in 1989, reported that Monascus sp also produced reductase inhibitors and subsequently obtained a patent (Steilberg, 2006; Endo, 2008). Figure 1. Structure of Lovastatin Pleiotropic Effects of Lovastatin The clinical applications of lovastatin have been well forms are hydrophilic for example atorvastatin, documented (Sreenivasan et al., 2008). It finds its fluvastatin, pravastatin (Zamvil and Steinmann., 2002). possible applications for more medical uses such as Lovastatin is obtained from different genera and reducing instances of peripheral vascular diseases, species of filamentous fungi. Several fungal genera prevention of strokes, stabilization of artheromatous including Aspergillus, Penicillium, Monascus, plaques, improved endothelial functions and prevention Paecilomyces, Trichoderma, Scopolariopsis, of thrombus formation (Tandon et al., 2005; Barrios and Doratomyces, Phoma, Phythium, Gymnoascus, Miranda, 2010). Hypomyces and Pleurotus are reported as lovastatin producers (Bizukojc and Stanislaw, 2009, Cabral et al., 2010, Srinu et al., 2010). In addition even the Alzheimers Disease (AD): Amyloid plaque formation in Basidiomycetes mushrooms have been recently reported brain is noted in patients with AD due to production of to be used. Pleurotus spp and its related strains produce neurotoxic amyloid protein (produced by alternate higher concentrations of lovastatin (Alarcon et al., 2003). processing of amyloid precursor protein). Animal and cell Recently, a marine actinomycete has also been reported culture experiments reported decreased prevalence of to produce lovastatin (Srinu et al., 2010). This review AD on lovastatin treatment (Eckert et al., 2005). Human gives an insight into lovastatin production by SSF in the trials did not yield 100% results and further work needs to last 5-6 years and the possible multiple (pleiotropic be warranted in the same area to attribute exact role of effects) applications of lovastatin in medical field. lovastatin (Eckert et al., 2005). HISTORY Multiple Sclerosis (MS): Lovastatin supressed production of tumor necreosis factor- α(TNF-α) by A US based company (in 1950’s), Wm. S. Merrell Co., Interferon-α (IFN-α). A decreased level of inflammatory reported a compound with anti-cholesterol property, response and protection of hosts cellular damage was called as Triparanol (MER/ 29) which blocked the noted. Lovastatin also inhibited major histocompatibiliy conversion of desmosterol to cholesterol. Later it was complex-II (MHC-II) upregulation in antigen presenting reported that triparanol was an ineffective drug and cells (APC’s). Atorvastatin prevented or reversed associated with lens cataracts, hair loss in rats and dogs, paralysis in murine experiemental autoimmune also higher doses causes blindness in rats (Steilberg, encephalitis (EAE) models thus indicating the 2006). This led to ban on triparanol. Masao Kuroda and immunomodulatory role of lovastatin (Zamvil and Akira Endo, supported by their team, at Sankyo Co. Steinmann, 2002). Tokyo, screened numerous fungi and discovered that Penicillium citrinum produced anti-cholesterol compound. This compound from P. citrinum was christened as Bone Disorders: In murine models prolonged infusions ML236B (referred to as compactin). With several tests or large doses of lovastatin stimulated bone formation the carcinogenic effects of compactin came to light due to both in-vivo and in-vitro (Sreenivasan et al., 2008). Pre- noted lymphomas in dogs treated with higher doses of clinical studies reported that nano particle delivery of compactin. This led to the said company to halt proposed lovastatin may fasten human bone fractures (Garrett et clinical trials. Later, Merck, a competitor, reported the al., 2007). This positive effect may also aid in treatment Praveen and Savitha 17 of osteoporosis (Sreenivasan et al., 2008). lov D. The multifunctional Polyketide Synthase (PKS) system encodes the LNKS and LDKS in A terreus. LNKS is a gene product of lov B, interacts with lov C (a putative Renal Protection: Glomerulonephritis associated kidney enoyl reductase) to form the dihydro monacolin L which is damage may be retarded by lovastatin treatment. This later converted to Monacolin J. The LDKS, gene product may be possibly due to down regulation of inflammatory of lovF, interacts with lov D (transesterase enzyme) that cytokines and activity of GTPases Ras superfamily. The catalyzes the attachment of the 2-methylbutyric acid to exact role of statins is yet to be elucidated (Buemi et al., monacolin J to form the functional lovastatin (Manzoni 2002). and Rollini, 2002, Sreenivasan et al., 2008, Barrios and Miranda, 2010). In tandem to this works on gene mutation and cloning Cancer: Induction of apoptotic response in human acute of lovastatin genes into other hosts have also been myeloid leukemia (AML) cells was noted on lovastatin reported (Pfeifer and Khosla, 2001, Xie and Tang, 2007). treatment (Xia et al.,2001). Inhibition of The possibility of conversion of Monacolin J (MCJ) to geranylgeranylation of target proteins is the mechanism simvastatin (a semisynthetic form of lovastatin) using lov of lovastatin-induced apoptosis in AML cells. The D gene that has been transferred to E coli has been antiproliferative properties of lovastatin may be used as reported (Xie and Tang, 2007). The substrate used for an effective anticancer drug (Tandon et al., 2005). The the lov D was α-dimethylbutyryl-S-NAC (or α- mechanism underlying lovastatin induced apoptosis of dimethylbutyryl-S-methylthioglycolate). However, this malignant cells remains unclear (Bonovas et al., 2006; reaction resulted in poor product turnout (Xie and Tang, Glynn et al., 2008). About 20 %– 55% reduction in site- 2007). Later,
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